Hypoxia in tumors contributes to chemotherapy resistance, worsened by acidosis driven by carbonic anhydrases (hCA IX and XII). Targeting these enzymes can mitigate acidosis, thus enhancing tumor sensitivity to cytotoxic drugs. Herein, novel 4-(pyrazolyl)benzenesulfonamide ureas (SH7a–t) were developed and evaluated for their inhibitory activity against hCA IX and XII. They showed promising results (hCA IX: K_I = 15.9–67.6 nM, hCA XII: K_I = 16.7–65.7 nM). Particularly, SH7s demonstrated outstanding activity (K_Is = 15.9 nM for hCA IX and 55.2 nM for hCA XII) and minimal off-target kinase inhibition over a panel of 258 kinases. In NCI anticancer screening, SH7s exhibited broad-spectrum activity with an effective growth inhibition full panel GI₅₀ (MG-MID) value of 3.5 μM and a subpanel GI₅₀ (MG-MID) range of 2.4–6.3 μM. Furthermore, SH7s enhanced the efficacy of Taxol and 5-fluorouracil in cotreatment regimens under hypoxic conditions in HCT-116 colorectal cancer cells, indicating its potential as a promising anticancer agent.

中文翻译：

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4-（吡唑基）苯磺酰胺脲作为碳酸酐酶抑制剂和缺氧介导的化疗增敏剂在结直肠癌细胞中的作用


肿瘤缺氧导致化疗耐药，碳酸酐酶 （hCA IX 和 XII） 驱动的酸中毒会加剧化疗耐药性。靶向这些酶可以减轻酸中毒，从而提高肿瘤对细胞毒性药物的敏感性。在此，开发了新型 4-（吡唑基）苯磺酰胺脲 （SH7a-t） 并评价了它们对 hCA IX 和 XII 的抑制活性。他们显示出有希望的结果 （hCA IX： K = 15.9–67.6 nM， hCA XII： K = 16.7–65.7 nM）。特别是，SH7s 在一组 258 种激酶中表现出出色的活性 （hCA IX 的 Ks = 15.9 nM，h CA XII 的 K s = 55.2 nM）和最小的脱靶激酶抑制。在 NCI 抗癌筛查中，SH7s 表现出广谱活性，有效生长抑制全面板 GI₅₀ （MG-MID） 值为 3.5 μM，子面板 GI₅₀ （MG-MID） 范围为 2.4-6.3 μM。此外，SH7s 增强了紫杉醇和 5-氟尿嘧啶在 HCT-116 结直肠癌细胞缺氧条件下联合治疗方案中的疗效，表明其作为一种有前途的抗癌剂的潜力。